For HIV infection, biomathematical approaches have been instrumental in generating testable hypotheses regarding viral persistence and evolution, in providing insights into viral dynamics and pathogenesis, and in the analysis of viral sequences. This has led to the collection of increasingly detailed and complex data on viral and host genetic variation, which necessitates the development of more biologically realistic mathematical and statistical models of HIV dynamics and evolution. At UCSD we have developed a number of translational research programs to investigate the natural history and pathogenesis of HIV infection. The award of R01 AI047745, "Biomathematical analysis of viral dynamics and evolution," provided mathematical and statistical support to interpret the data and to aid in the design of new studies. We propose to continue to develop biomathematical models to help interpret viral and host genetic variation in the context of escape from therapy and the immune system, integrating these models into several clinical studies of HIV infection in a variety of settings relevant to the care of HIV infected individuals: 1. Full-length sequences of the HIV-1 genome will be obtained from individuals with recent HIV infection in order to describe the natural history of viral evolution during the early stages of infection at a genome-wide level. 2. High resolution human leukocyte antigen (HLA) haplotypes and various genetic polymorphisms involved in immune responses will be obtained from individuals with recent HIV infection. These data will be used to determine the role of host genetic variation in driving escape mutations and the natural history of HIV. 3. A large dataset of viral genotypes, phenotypes and clinical data from over 1000 subjects in the HIV Cost and Services Utilization study will be used to generate statistical models of the correlations between viral genotype, phenotype, viral load, and therapeutic regimen. These models will provide information on how HIV evolves resistance to multiple antiviral agents, and the impact of viral resistance mutations on viral fitness. 4. We will study viral dynamics and evolution in (a) the male genital tract and (b) cerebrospinal fluid. As genital secretions are the major source of transmitted HIV, information on the compartmentalization of HIV within the male genital tract will help us understand the biological determinants of HIV transmission. HIV in the central nervous system is associated with HIV dementia;we will investigate genetic changes in the virus associated with a neurotropic phenotype.